Clinical, genetic, and familial features of POT1 tumor predisposition syndrome

Abstract

Background

Protection of telomere 1 (POT1) tumor predisposition syndrome (POT1‐TPD) is a hereditary leukemia syndrome that is identified in ∼5% of patients with chronic lymphocytic leukemia (CLL) and is characterized by a predisposition to other cancers, including gliomas, melanomas, and angiosarcomas. This study reports clinical and genetic characteristics of a large cohort of individuals with POT1‐TPD.

Materials and Methods

Individuals with pathogenic/likely pathogenic germline POT1 variants referred to the Hereditary Hematologic Malignancy Clinic at The University of Texas MD Anderson Cancer Center were included. Individuals with variants of uncertain significance were included if found to have telomeres >90th percentile of age‐predicted length.

Results

Twenty‐four individuals in 17 families were identified. At referral, 11 (46%) had CLL and one (4%) had monoclonal B‐cell lymphocytosis (MBL). The remaining 12 individuals had no history of CLL/MBL; however, four (33%) were discovered to have MBL at the time of referral. Among the 17 families, melanoma (47%), CLL (35%), and glioblastoma (18%) were prevalent. Five families had telomere length testing (31%), with lymphocyte telomere lengths >99th percentile in 60% and >90th percentile in 100%. Patients with CLL (n = 11) had a median age at diagnosis of 55 years (range, 29–68). A total of 82% had diploid karyotype, 64% had del13q by fluorescence in situ hybridization, and 60% had mutated immunoglobulin heavy chain variable region. Five patients (45%) received treatment for CLL, with a median time‐to‐treatment of 4.5 years (95% CI, 4.3–4.6).

Conclusion

This analysis provides insights into the clinical features and familial patterns of malignancy of individuals with POT1‐TPD. Identification through genetic counseling and augmented cancer screening is paramount.

Short abstract

This analysis provides insights into the clinical features, genetic profile, and familial patterns of malignancy of individuals with POT1‐TPD. Identification through genetic counseling and augmented cancer screening is paramount for these individuals.

INTRODUCTION

There is an increasing recognition of hereditary leukemia predisposition syndromes underlying the development of both myeloid and lymphoid hematologic malignancies. Current estimates suggest 5%–10% of hematologic malignancies may have an underlying germline component, similar in incidence to breast, prostate, and colon cancers. The revised World Health Organization (WHO) ¹ as well at the International Consensus Classification (ICC) ² and European LeukemiaNet (ELN) ³ guidelines now recognize underlying hereditary hematologic malignancies (HHM) as a unique entity, raising awareness of germline predispositions that may directly impact patient care, such as optimal transplant donor selection, as well as identification of family members who may benefit from genetic counseling and both screening and preventive approaches.

Chronic lymphocytic leukemia (CLL) represents approximately 1% of all new cancer cases per year in the United States. It is more common in males, people of European ancestry, and in older individuals, with a median age at diagnosis of 70 years. ⁴

The entity of “familial CLL,” defined as a patient with CLL with at least one additional relative with CLL, has long been recognized, with population‐based samples suggesting an incidence of ∼5%–8%. ⁵ Data from the Swedish Family‐Cancer Database have identified that family members of an individual affected with CLL/SLL have a 5.6× increased lifetime risk of CLL, as well as an increased risk of other lymphoid malignancies such as non‐Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). ⁶ The incidence of monoclonal B‐cell lymphocytosis (MBL) is also increased in relatives of patients with CLL, with an incidence of 13.5%–18% in unaffected first‐degree relatives, compared to a general population where MBL incidence is approximately 3.5% among adults with normal blood counts. ⁷ , ⁸ , ⁹

Familial CLL risk appears to be mostly multifactorial, as identifiable single‐gene Mendelian predispositions to lymphoid malignancies remain rare. ¹⁰ One notable exception is protection of telomere 1 (POT1), a key gene within the shelterin telomere complex that functions to maintain chromosome stability and prevent inappropriate activation of the DNA damage response at telomeres. ¹¹ , ¹² POT1 variants occur in approximately 5% of patients with CLL and are more common among patients with unmutated immunoglobulin heavy chain variable region (IGHV) status. ¹³ POT1 variants are typically somatically acquired, however, germline POT1 variants have been described in families with familial CLL consistent with POT1 tumor predisposition syndrome (POT1‐TPD). ¹⁴ POT1‐TPD is characterized by a personal and/or family history of gliomas, cutaneous melanomas, angiosarcomas, cardiac myxomas, and CLL, ¹⁵ , ¹⁶ , ¹⁷ with emerging association with an increased risk for thyroid cancer and colorectal cancer. ¹⁸ A link with JAK2‐mutated MPNs has also been proposed. ¹⁹ , ²⁰

Although POT1‐TPD is an established entity, the clinical characteristics, natural history, and treatment outcomes of individuals harboring germline POT1 variants have not been yet described, and recommendations for additional cancer surveillance remain inadequately defined. In this study, we analyzed a large cohort of individuals with POT1‐TPD. We reviewed their personal and familial cancer history and described the POT1 variants observed. We searched for the presence of MBL populations by flow cytometry among patients with POT1‐TPD and reviewed the disease characteristics, clinical course, and response to therapy in POT1‐TPD patients with CLL.

MATERIALS AND METHODS

Patients with a POT1 gene variant, identified during workup of a hematologic malignancy or as part of familial cascade testing, were referred to the Hereditary Hematologic Malignancy Clinic (HHMC) at The University of Texas MD Anderson Cancer Center in Houston, Texas. To confirm that the POT1 variant was germline, clinical laboratory genetic testing was performed on blood or saliva for individuals without a hematologic malignancy or cultured skin fibroblasts for patients with a hematologic malignancy. Specifically, germline testing for POT1 gene mutations was performed either by GeneDx using Next‐generation Sequencing (NGS) on genomic DNA extracted from blood, saliva, or cultured fibroblasts via skin punch biopsy ²¹ or by Invitae if genomic DNA was extracted from blood or saliva.

Patients determined to have a germline pathogenic or likely pathogenic (P/LP) variant POT1 gene were included in this study. Patients heterozygous for a variant of uncertain significance (VUS) in the POT1 gene were only included if the patient was also found to have long telomeres >99th percentile for age‐matched controls, as telomerase‐dependent elongation of telomeres has been hypothesized to be the pathogenic mechanism of P/LP POT1 variants. ¹⁹ The study period was July 14, 2015, to December 10, 2024.

Telomere length testing was performed via flow cytometry and fluorescence in situ hybridization (FISH) (flow‐FISH) by Johns Hopkins Hospital Laboratories, and the data were plotted relative to a clinically validated nomogram. ²² Clinical, laboratory, and genetic features of patients were collected using a standardized case report form. As POT1‐TPD is associated with a broad spectrum of hematologic and nonhematologic malignancies, personal and family cancer histories were systemically collected with detailed three‐generation pedigrees created for each individual.

The primary end point of this study was descriptive characterization of POT1‐TPD, including the spectrum of germline POT1 variants and associated personal and familial cancer phenotypes. Secondary end points included the clinical characteristics, disease course, and treatment outcomes of individuals with POT1‐associated CLL and MBL. Time‐to‐event analyses were performed using the Kaplan–Meier estimate. Overall survival (OS) was measured from the time of CLL diagnosis to the time of last follow‐up or death from any cause. All statistical analyses were performed using SPSS (IBM Corp., Armonk, New York) software.

RESULTS

Study population

Twenty‐four individuals in 17 families with heterozygous P/LP POT1 variants or VUS in POT1 with long telomeres were identified (Table 1). At the time of HHMC referral, 11 individuals (46%) had an established diagnosis of CLL and one individual (4%) had an established diagnosis of MBL. The remaining 12 individuals (50%) had no history of CLL or MBL; these individuals and were referred to HHMC based on the detection of a POT1 variant due to workup of another malignancy (two individuals had a personal history of melanoma) or as part of family cascade testing (two individuals had a family history of CLL and eight individuals had a family history of non‐CLL cancer). Among the 12 individuals without a preexisting history of CLL or MBL, peripheral blood flow cytometry performed at the time of referral revealed MBL in an additional four individuals (33%).

TABLE 1.

Baseline characteristics of individuals with POT1‐TPD (n = 24).

	No. (%)
Demographics
Age in years, median (range)	61 (9–80)
Male, No. (%)	11 (46)
Diagnosis
MBL	5 (21)
Presence of additional malignancy	4 (80)
CLL	11 (46)
Presence of additional malignancy	6 (55)
Other malignancies	Total (n = 24)	MBL (n = 5)	CLL (n = 11)
Skin
Melanoma	6 (25)	2 (40)	2 (18)
Squamous cell carcinoma	2 (8)	1 (20)	1 (9)
Basal cell carcinoma	2 (8)	0 (0)	2 (18)
Other hematologic
Mycosis fungoides	1 (4)	0 (0)	1 (9)
CML	1 (4)	1 (20)	0 (0)
Marginal zone lymphoma	1 (4)	0 (0)	0 (0)
Breast cancer	3 (13)	2 (40)	1 (9)
Neuroendocrine tumor	2 (8)	0 (0)	2 (18)
Prostate adenocarcinoma	1 (4)	0 (0)	1 (9)
Papillary thyroid cancer	1 (4)	0 (0)	1 (9)
Lung adenocarcinoma	1 (4)	0 (0)	1 (9)
Hepatocellular carcinoma	1 (4)	0 (0)	1 (9)
Testicular cancer	1 (4)	0 (0)	1 (9)
Pleomorphic adenoma of the parotid gland	1 (4)	0 (0)	1 (9)
Benign thyroid disease
Hypothyroidism	7 (29)	1 (20)	6 (55)
Multinodular goiter	1 (4)	0 (0)	1 (9)

Abbreviations: CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; MBL, monoclonal B‐cell lymphocytosis; POT1‐TPD, protection of telomere 1 tumor predisposition syndrome.

POT1 variant analysis

Details of the POT1 variants were available for 16 of 17 families (Table 2). Variants were classified as pathogenic (7 of 16, 44%), likely pathogenic (7 of 16, 44%), or VUS (2 of 16, 19%). The VUS variants were included in this analysis due to confirmed telomere lengths greater than the 99th percentile by flow‐FISH of sorted lymphocytes. Across the 16 families, 13 unique POT1 variants were identified; three unrelated families had identical DNA changes. Specific variants are represented visually in Figure 1.

TABLE 2.

POT1 variant characteristics identified in 16 unique families with POT1‐TPD.

Family number	Testing source	DNA variant	Resulting change	Classification	Additional germline variants	Lymphocyte telomere percentile	Granulocyte telomere percentile
1	Skin	c.265_273delinsAATCCT (p.Y89_K91delinsNL)	In‐frame deletion of three amino acids and insertion of two amino acids in a nonrepeat region	Likely pathogenic	None	—	—
2	Skin	c.1071dup (p.Q358Sfs*13)	Frameshift mutation resulting in truncation or nonsense‐mediated decay	Pathogenic	None	—	—
3	Skin	c.818 G>A (p.R273Q)	Missense mutation with deleterious effect on protein structure/function	Likely pathogenic	None	>99	—
4	Skin	c.314C>T (p.Q358fs)	Missense mutation with unknown effect on protein structure/function	VUS	None	>99	90–99
5	Skin	c.1071dup (p.Q358Sfs*13)	Nonsense mutation	Pathogenic	CHEK2 (pathogenic)	—	—
6	Saliva	c.1163+1G>A (p.T105M)	Mutation leading to disruption of splice site	Likely pathogenic	MIFT (pathogenic)	—	—
7	Skin	c.147del (p.I49Mfs*7)	Frameshift mutation resulting in truncation or nonsense‐mediated decay	Likely pathogenic	None	—	—
8	Skin	c.1087C>T (p.R363X)	Nonsense mutation	Pathogenic	TERT (likely benign)	—	—
9	Skin	c.799G>A (p.G267R)	Missense mutation with unknown effect on protein structure/function	VUS	None	>99	—
10	Skin	c.265T>C (p.Y89H)	Missense mutation with unknown effect on protein structure/function	Likely pathogenic	None	—	—
11	Skin	c.1851_1852del (p.D617Efs*9)	Frameshift mutation resulting in truncation or nonsense‐mediated decay	Likely pathogenic	None	—	—
12	Blood	c.119G>T (p.G40V)	Missense mutation with unknown effect on protein structure/function	Likely pathogenic	Unknown	—	—
13	Saliva	c.1087C>T (p.R363*)	Nonsense mutation	Pathogenic	NF1 (VUS)	90–99	90–99
14	Skin	c.1164‐1G>A	Mutation leading to disruption of splice site	Pathogenic	GALNT12 (VUS), IKZF1 (VUS)	—	—
15	Skin	c.1164‐1G>A	Mutation leading to disruption of splice site	Pathogenic	Unknown	—	—
16	Blood	c.910dup (p.D340Gfs*9)	Nonsense mutation	Pathogenic	BRCA2 (pathogenic)	90–99	50

Abbreviations: POT1‐TPD, protection of telomere 1 tumor predisposition syndrome; VUS, variant of uncertain significance.

FIGURE 1.

POT1 variants observed across 16 unique families with protection of telomere 1 tumor predisposition syndrome.

Additional germline pathogenic variants were observed in three families (19%): CHEK2, BRCA2, and MITF. The family with a concurrent BRCA2 variant had a high prevalence of breast cancer (five affected out of 11 known family members), including two cases of breast cancer occurring at age <40 and two cases of male breast cancer. The family with a concurrent CHEK2 variant had one individual with breast cancer (age 40) out of 16 known family members. The family with a concurrent MITF variant had two individuals with melanoma out of eight known family members.

Telomere length testing by flow‐FISH was performed in five individuals from different families (31%). All individuals had lymphocyte telomere lengths above the 90th percentile and 60% exceeded the 99th percentile (Figure S1). Of the five individuals tested, two had CLL, two had MBL, and one had no lymphoproliferative disorder.

Personal and familial cancer history

Personal cancer history

Eleven of 24 individuals with POT1‐TPD (46%) had at least one non‐CLL/MBL malignancy, including 10 cases of skin cancer (six melanoma and four nonmelanoma), three cases of estrogen receptor (ER)/progesterone receptor (PR) positive breast cancer, three cases of non‐CLL/MBL hematologic cancer (one mycosis fungoides, one CML, and one marginal zone lymphoma), and one case of papillary thyroid cancer (Table 1). Benign thyroid disease was present in eight individuals (33%). No glioblastoma or angiosarcoma were observed.

The rate of additional cancers was higher in those with CLL/MBL (10 of 16, 63%) than in those without (3 of 8, 38%). The most frequent additional cancers in patients with CLL/MBL were skin cancer (eight patients; four melanoma and four nonmelanoma histology) and ER/PR positive breast cancer (three patients).

Family cancer history and familial country of origin

Family cancer history of the 17 families is outlined in Table 3. The most frequent familial cancers were melanoma (8 of 17, 47%) and CLL (6 of 17, 35%). Cases of glioblastoma (3 of 17, 18%) and papillary thyroid cancer (3 of 17, 18%) were also reported. In addition, cancers of the breast (82%), colon (29%), stomach (29%), and lung (24%) were common. Family pedigrees are available in the Supporting Information (Figure S2A–R).

TABLE 3.

Prevalence of malignancy in 17 unique families with POT1‐TPD (n = 17).

Cancer type	No. of families with one or more cases, No. (%)
Skin cancer
Melanoma	8 (47)
SCC	2 (12)
BCC	1 (6)
Hematologic cancer
HL	1 (6)
NHL	5 (29)
CLL	6 (35)
MM	1 (6)
CML	1 (6)
T‐PLL	1 (6)
Brain cancer
Glioblastoma	3 (18)
Neuroblastoma	1 (6)
Sarcoma
Osteosarcoma	1 (6)
Angiosarcoma	1 (6)
Breast cancer	14 (82)
Colon cancer	5 (29)
Gastric cancer	5 (29)
Lung adenocarcinoma	4 (24)
Papillary thyroid cancer	3 (18)
Prostate adenocarcinoma	3 (18)
Bladder cancer	3 (18)
Hepatocellular carcinoma	2 (12)
Renal cell carcinoma	2 (12)
Testicular cancer	2 (12)
Cervical cancer	1 (6)
Pancreatic cancer	1 (6)
Esophageal cancer	1 (6)

Abbreviations: BCC, basal cell carcinoma; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MM, multiple myeloma; NHL, non‐Hodgkin lymphoma; POT1‐TPD, protection of telomere 1 tumor predisposition syndrome; SCC, squamous cell carcinoma; T‐PLL, T‐cell prolymphocytic leukemia.

Self‐reported familial country of origin information was available for eight individuals (33%) (Table S1). The majority of these eight individuals indicated a European country of origin, although three individuals reported Native American ancestry. Information regarding Ashkenazi Jewish descent and consanguinity was available for the entire cohort of 24 patients; neither was reported by any individual.

Clinical characteristics of the CLL/MBL cohort

MBL characteristics

The POT1‐TPD patients with MBL (n = 5) had a median age at diagnosis of 66 years (range, 40–68). Characteristics of these patients are outlined in the Supporting Information (Table S2). Cytogenetic analysis (available in three cases) revealed diploid karyotypes;del(13q) was detected in three of five patients by FISH. IGHV mutation status was available for two patients: one mutated and one unmutated. One 54‐year‐old patient who had been diagnosed with MBL at the time of HHMC referral progressed to CLL at 12.0 months from MBL diagnosis. Investigations at the time of CLL progression were significant for deletion 13q on FISH and an unmutated IGHV.

CLL characteristics

The POT1‐TPD patients with CLL (n = 11) had a median age at diagnosis of 55 years (range, 29–68). Characteristics of these patients are outlined in Table 4. Most had diploid cytogenetics (82%), with del13q present by FISH in 64%. IGHV mutation status was performed in 10 patients (60% mutated and 40% unmutated). Seven patients underwent NGS testing as part of the evaluation of prognostic markers for CLL. When we compared the NGS results with prior germline testing, NGS was concordant in five of seven patients; in two cases, NGS did not detect the germline POT1 variant as the variants occurred in codons not covered by our institutional NGS assay. No patients harbored a second somatic POT1 mutation. Additional somatic mutations were present in six of seven patients, most commonly NOTCH1 (43%).

TABLE 4.

Characteristics of patients with CLL and POT1‐TPD (n = 11).

	No. (%)
Demographics
Age in years at diagnosis, median (range)	55 (29–68)
Laboratory values at diagnosis
WBC count, ×109/L, median (range)	23.9 (13.7–155.8)
Absolute lymphocyte count, ×109/L, median (range)	26.1 (5.9–143.3)
Hemoglobin, g/dL, median (range)	13.4 (10.6–16.7)
Platelet count, ×106/L, median (range)	176 (65–297)
Genetic profile at diagnosis
FISH, No. (%)
Del13q	7 (64)
Normal	3 (27)
Trisomy 12	2 (18)
Del17p	1 (9)
Del11q	0 (0)
IGHV status, No. (%)
Mutated	6/10 (60)
Unmutated	4/10 (40)
Cytogenetics, No. (%)
Diploid	9 (82)
Complex a	0 (0)
NGS, No. (%)
Somatic comutations	6/7 (86)
NOTCH1	3/7 (43)
FAT1	2/7 (29)
MUC2	1/7 (14)
JAK2	1/7 (14)
TP53	0/7 (0)

Abbreviations: CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy chain variable region; MBL, monoclonal B‐cell lymphocytosis; NGS, Next‐generation Sequencing; POT1‐TPD, protection of telomere 1 tumor predisposition syndrome; WBC, white blood cell.

^a Complex cytogenetics is defined as three or more additional clonal abnormalities.

CLL treatment and outcomes

At a median follow‐up of 8.2 years, the median OS for all CLL patients (treated and untreated) was 13.8 years (95% CI, 9.4–18.3). Three patients (27%) died due to causes unrelated to CLL (gastrointestinal bleeding, diabetic ketoacidosis, and progression of metastatic lung cancer); the remaining eight patients remain alive.

Five patients (45%) have received treatment to date, with a median time‐to‐treatment of 4.5 years from CLL diagnosis (95% CI, 4.3–4.6); six patients (55%) remain on observation. Treated patients received a median of two lines of therapy (range, 1–9). Details of initial treatment, response, and time‐to‐next treatment (TTNT) after initial therapy are summarized in Table S3.

DISCUSSION

This comprehensive analysis includes a review of a large cohort of germline POT1 variants and provides further insight into familial patterns of malignancy. Additional details are provided regarding somatic mutations in patients with CLL and POT1‐TPD, including telomere length analyses, incidence of concurrent germline and somatic mutations, response to treatment, and survival. Furthermore, two of the families in our cohort have POT1 VUS that likely represent newly identified pathogenic mutations.

Families studied in this analysis had a high prevalence of CLL, melanoma, and glioblastoma, in keeping with what has been previously reported in the literature in subjects with POT1‐TPD. Breast, lung, and colon cancer were also commonly observed in our cohort; however, given the high prevalence of these cancers in the general population, additional families will need to be studied to determine a causal relationship. An interesting finding was the presence of concurrent pathogenic variants in several families, including CHEK2 in one family, BRCA2 in one family, and MIFT in one family. The cancer prevalence observed in these families was in keeping with what would be expected with each pathogenic germline variant; several family members were affected by breast cancer in the family with the BRCA2 variant and two individuals with melanoma were observed in the family with MIFT variant. Co‐occurrence of these mutations with POT1 has not been previously described and it is important to be aware that multiple germline cancer predisposition syndromes may be present in the same family.

It is notable that among the 12 individuals who were referred to HHMC based on the identification of a POT1 variant due to workup of another malignancy or due to family cascade testing, four were found to have MBL. These patients had no known history of CLL or MBL. This is a particularly high rate of detection, considering the median age of these four individuals was 60 years (range, 40–68). This highlights the importance of identifying and screening these patients for the presence of an MBL clone for the purpose of infection prevention, cancer screening, and monitoring for progression of the MBL to CLL. Further supporting this is the recent review by Brock et al. ²³ of 23 unrelated patients with 10 unique POT1 variants; in their cohort, individuals with LP/P POT1 variants had a 16.6‐fold increased likelihood of being diagnosed with CLL compared to their POT1‐negative counterparts.

Our cohort of patients with CLL was younger than average, ²⁴ with a median age at diagnosis of 55 years. This finding likely represents an earlier age of development of CLL, which can be seen in many hereditary cancer predisposition syndromes and has also been described in patients with familial CLL. The most common cytogenetic alteration observed on FISH was del13q and IGHV was mutated in 60% of patients, suggesting that patients with CLL and POT1‐TPD have similar features to the POT1 wild‐type CLL. Although our numbers are small, our experience suggests that CLL occurring in patients with POT1‐TPD does not appear to be associated with TP53 mutation or refractoriness to therapy.

Additional somatic mutations by NGS were found in six of seven tested patients with CLL and POT1‐TPD. The most common somatic comutation noted was NOTCH1 in 43% of patients, which has been shown to be associated with a shorter time to first treatment in CLL and an increased risk for Richter’s transformation. ²³ Although a link between JAK2 and POT1 has been previously suggested, ¹⁹ this comutation was only observed in one patient in our cohort.

Of substantial interest, all individuals with POT1‐TPD who had telomere length testing performed had telomeres above the 90th percentile (and of these, 43% were above the 99th percentile). This finding is in agreement with the report by Deboy et al. ¹⁹ of 23 germline POT1 variant carriers from eight families. This report also identified high rates of B‐cell and T‐cell lymphoproliferative disease in addition to long telomeres (greater than the 99th percentile in 9 of 13 patients tested), supporting the hypothesis that POT1 is a gene that confers cancer risk via extending cellular lifespan and promoting clonal evolution.

We acknowledge that the inclusion of two individuals with POT1 VUS represents a potential limitation of this study. In addition to confirming that both individuals exhibited markedly long telomeres, we sought additional information regarding these variants from the testing laboratories. The POT1 c.314C>T (p.Thr105Met) variant lies within a highly conserved variant of the gene, and although rare, has been reported in one other case of an individual with multiple primary melanomas. ²⁵ In silico analyses suggest that this missense variant does not alter protein function. The POT1 c.799 (p.Gly267Arg) variant also occurs in a highly conserved region and is predicted to impact protein function; however, this variant has not been previously reported in individuals with a phenotype consistent with POT1‐TPD. Although the available evidence is limited and partly discordant, we consider these variants plausibly pathogenic given the elongated telomeres observed and the presence of POT1‐associated malignancies within these families.

Nearly a decade after the initial report by Speedy et al. ¹⁴ of the association between familial CLL and germline mutations in shelterin complex genes, the ability to correctly identify patients with CLL and POT1 germline variants has become increasingly important. Not only do these patients require additional screening for an increased risk of various solid tumors, but referral to a genetic counselor for consideration of genetic testing for potentially affected family members is vital. To date, no formal guidelines for cancer screening in individuals with germline POT1‐TPD have been established.

Based on our experience and clinical practice, we currently recommend that at time of referral these patients undergo flow cytometry testing from the peripheral blood to evaluate for the presence of an MBL clone. A complete blood count (CBC) and physical examination, including lymph node examination, should be performed annually. In addition to the US Preventative Services Task Force recommendations for cancer screening, these individuals should also undergo the following: a full skin examination by a dermatologist every year (consider every 3–6 months in patients with a history of atypical nevi or family history of melanoma), an echocardiogram every 2–3 years (or more frequently in patients with a family history of angiosarcoma), and an MRI of the brain every 2–3 years (or more frequently in patients with a family history of glioma).

We acknowledge that these recommendations are currently the opinion of the authors and not yet a consensus recommendation from any specific body, and there remains a need for validation of our suggested surveillance strategies on a larger scale. Despite this, we hope that sharing our findings regarding families with POT1‐TPD will be helpful to clinicians tasked with managing these patients.

AUTHOR CONTRIBUTIONS

Courtney D. DiNardo: Conceptualization, methodology, writing–original draft, and writing–review and editing. Jennifer Croden: Investigation, writing–original draft, and writing–review and editing. Hiam M. Abdel‐Salam: Methodology and writing–review and editing. Tapan Kadia: Writing–review and editing. Matteo Molica: Writing–review and editing. Alexandre Bazinet: Writing–review and editing. Prithviraj Bose: Writing–review and editing. Abhishek Maiti: Writing–review and editing. Fadi Haddad: Writing–review and editing. Jan Burger: Writing–review and editing. Hagop Kantarjian: Writing–review and editing. William Wierda: Writing–review and editing. Nitin Jain: Writing–review and editing. Alessandra Ferrajoli: Conceptualization, methodology, writing–original draft, and writing–review and editing .

CONFLICT OF INTEREST STATEMENT

Prithviraj Bose reports consulting fees from AbbVie, Blueprint Medicines Corporation, Bristol‐Myers Squibb, Cogent BioSciences, CTI BioPharma, Dainippon Sumitomo Pharma, Disc Medicine, Geron Corporation, GlaxoSmithKline, Incyte Corporation, Ionis Pharmaceuticals, Jubilant Therapeutics, Karyopharm Therapeutics Inc, Keros Therapeutics, Merck Sharp and Dohme, Morphic Therapeutic, Morphosys, Novartis, Pharma Essentia, Raythera, Sobi, Inc, and Takeda Oncology; fees for other professional activities from GlaxoSmithKline and Merck Sharp and Dohme; grant and/or contract funding from Ajax Therapeutics, Blueprint Medicines Corporation, Bristol‐Myers Squibb, Cogent BioSciences, CTI BioPharma, Dainippon Sumitomo Pharma, Disc Medicine, Geron Corporation, Incyte Corporation, Ionis Pharmaceuticals, Janssen Biotech, Inc, Kartos Therapeutics, Karyopharm Therapeutics Inc, Morphosys, and Telios. Jan Burger reports fees for other professional activities from BeiGene USA, Inc and Pharmacyclics LLC; grant and/or contract funding from AbbVie, AstraZeneca AB, and BeiGene USA, Inc; and travel fees from Janssen Global Services, LLC. Courtney DiNardo reports consulting fees from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol‐Myers Squibb, Daiichi Sankyo Company, GlaxoSmithKline, Jazz Pharmaceuticals, Notable Labs, Rigel Pharmaceuticals, Inc, Ryvu, and Servier Pharmaceuticals LLC; and fees for data and safety monitoring from Genmab. Nitin Jain reports consulting fees from Adaptive Biotechnologies Corporation, BeiGene USA, Inc, Bristol‐Myers Squibb, and Takeda Oncology; gifts from AbbVie, AstraZeneca, Cellectis, Genentech, and Gilead Sciences Inc; grant and/or contract funding from AbbVie, ADC Therapeutics, AstraZeneca, Cellectis, Fate Therapeutics, Genentech, Gilead Sciences Inc, and Pharmacyclics LLC; and travel funding from Pharmacyclics LLC. Tapan Kadia reports consulting fees from AbbVie, Agios Pharmaceuticals, Inc, Daiichi Sankyo, Genentech, Novartis, Servier Pharmaceuticals LLC, and Syndax; grant and/or contract funding from Ascentage Pharma, Bristol‐Myers Squibb, Genentech, Incyte Corporation, and Jazz Pharmaceuticals. William G. Wierda reports grant and/or contract funding from AbbVie Inc, Acerta Pharma, Bristol‐Myers Squibb, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, Loxo Oncology Inc, Pharmacyclics LLC, Nurix Therapeutics, and BeiGene; honoraria from Intellisphere, Physicians Education Resource, MD Education, PLS, AJMC, Research to Practice, Curio Science, Total Health, the University of Nebraska Medical Center, Peer Direct, Cancer Network; fees for attending meetings and/or travel from Research to Practice, MD Education, the University of Nebraska Medical Center, Lilly, Bio Ascend, Hematology Society of Taiwan, German CLL Study Group; participation on a data safety monitoring board or advisory board for AZ, AbbVie, Acerta Pharma, BeiGene/BeONe, BMS, Eli Lilly, Wiley China, Intellisphere, LOXO/Lilly, Johnson and Johnson, Genmab; and a leadership or fiduciary role in other board, society, committee or advocacy group for iwCLL and the National Comprehensive Cancer Network. The other authors declare no conflicts of interest.

Supporting information

Supplementary Material

DiNardo CD, Croden J, Abdel‐Salam HM, et al. Clinical, genetic, and familial features of POT1 tumor predisposition syndrome. Cancer. 2026;e70315. doi: 10.1002/cncr.70315

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.